JP7797379B2 - Isosorbide taste masking - Google Patents

Description

This technology relates to masking the taste of isosorbide, particularly its bitter taste. Therefore, the technology developed herein proposes a new dosage form that makes it possible to improve the taste of isosorbide, and a process for preparing this dosage form.

Most active substances used in pharmaceutical forms intended for oral administration are characterized by an unpleasant taste. However, in recent years, taste has become an essential criterion, as it makes drug administration acceptable and improves treatment compliance. Taste masking is therefore a real challenge for drug developers, especially for drugs intended for pediatric and geriatric populations, for which oral administration is always relatively difficult. There are many taste-masking techniques available for drug formulations based on different approaches. There is no single definitive method, with the choice of technique depending primarily on the active substance to be masked, the pharmaceutical form, and the cost of the technology in question. These techniques are distinguished by simple methods, such as the addition of flavorings or sweeteners, which are often insufficient and require the use of more complex techniques, such as the use of cyclodextrins or ion-exchange resins.

Isosorbide is an osmotic diuretic used in several countries in the treatment of Meniere's disease. This active ingredient, which must be taken in large quantities, is known for its very unpleasant taste, particularly its strong bitter taste. Typically, a dose of isosorbide consists of a 40 mL stick for oral absorption containing 70% isosorbide (i.e., 28 g of isosorbide administered per dose). However, to date, no method has been found that allows for effective masking of the taste of isosorbide, especially considering the concentrations and amounts ingested.

OBJECTS OF THE INVENTION It is therefore an object of the present invention to provide an effective means for the taste masking of isosorbide, especially when this active ingredient is administered in large amounts and/or in high concentrations.

In this specification, the inventors propose a dosage form that makes it possible to solve this problem. This oral dosage form is in the form of gelling beads of isosorbide, preferably using alginate as the gelling agent.

As will become apparent from the examples below, this method allows for the administration of large amounts of isosorbide without the patient perceiving an unpleasant taste. The gelling beads thus obtained can contain more than 80% isosorbide by weight.

Furthermore, by reading the examples below, it will be observed that the methods of the present invention advantageously succeed where traditional taste-masking techniques, such as the use of sweeteners, flavorings, or cyclodextrins, have failed.

Furthermore, the dosage form proposed by the present invention is easy to implement because it does not require the use of many ingredients.

Given that isosorbide is a small, highly soluble molecule, it is surprising to observe that no bitter taste is perceived, especially considering the amount and concentration administered. Indeed, isosorbide diffuses out of the beads and into the saliva of the oral cavity so rapidly that its bitter taste would be expected to be detected by the taste buds and thus perceived by a panel of tasters.

For example, publication WO 2006/001344 relates to a gelling preparation based on isosorbide alginate and other gelling components. Such a composition is not suitable for producing beads. Furthermore, this document teaches that taste masking is optimized by adding cocoa powder. Publication U.S. Patent Application Publication No. 2010/120712 relates to a composition comprising these two components, the composition being in the form of extruded granules or powder. Compositions in the form of beads are not described.

The use of gelling alginate beads to mask the taste of active ingredients has been mentioned in the prior art. However, this technology has never been proposed to be applied to isosorbide to mask its taste. There is no suggestion in the prior art that this technology is applicable to isosorbide, especially considering that significant amounts of isosorbide are administered.

For example, publication WO 00/06122 describes a pharmaceutical composition for oral administration comprising particles of an active ingredient and a gelling agent. The particles of the active ingredient may optionally be in the form of alginate beads (Example 12). The resulting particles of the active ingredient are mixed with a gelling agent and other substances to obtain the final dosage form. During administration, this solid form is added to water to obtain a gelled composition, masking the unpleasant taste of the active ingredient. This publication does not mention isosorbide, and the final ingested pharmaceutical composition contains very small amounts of the active ingredient.

SUMMARY OF THE INVENTION Accordingly, firstly, the present invention relates to gelling beads comprising isosorbide, particularly for oral administration, having an isosorbide content of at least 50% isosorbide by dry weight relative to the total weight of the gelling beads.

Secondly, the present invention relates to a pharmaceutical composition comprising or consisting of the gelling beads of the present invention.

Third, the present invention provides a process for preparing the gelling beads of the present invention, comprising:
Step (a): preparing a solution comprising isosorbide and one or more gelling agents;
Step (b): preparing a gelling solution;
step (c) adding the solution prepared in step (a) dropwise to the gelling solution prepared in step (b);
Step (d) recovering the gelled beads of isosorbide thus obtained;
The present invention relates to a process including:

Fourthly, the present invention relates to a method for masking the unpleasant taste of isosorbide, which comprises incorporating the isosorbide into the form of gelling beads.

The features disclosed in the following paragraphs may be implemented optionally. They may be implemented independently of each other or in combination with each other.

First, the present invention relates to gelling beads containing isosorbide, particularly for oral administration, which have an isosorbide content of at least 50% by dry weight of isosorbide relative to the total weight of the gelling beads. Preferably, this isosorbide content by dry weight is at least 60%, preferably at least 70%, preferably at least 75%, more preferably even at least 80%. This isosorbide content by dry weight is generally not more than 95%, or even not more than 90%, or even not more than 85%.

This content of isosorbide by dry weight relative to the total weight of the gelling beads can be determined by one skilled in the art, for example, by gas chromatography using flame ionization detection and an internal standard method, preferably using methyl α-D-glucopyranoside as an internal standard, for example, according to the protocol described in the examples below.

Gelling beads of the present invention typically contain one or more gelling agents. Gelling agents capable of rapid gelation at ambient temperature and in the presence of water are particularly useful herein. These are preferably polymers capable of gelation by cross-linking in the presence of polyvalent metal ions.

Gelling agents include, inter alia, agents capable of gelling when used in combination. Examples of gelling agents are alginates, pectinates, carrageenans, and gelatins. Use is preferably not made of gelatin, especially due to the fact that gelatin is an animal-derived product. Use is preferably made of at least alginates as gelling agents. When multiple gelling agents are present, the proportion of alginates is at least 20% by weight, preferably at least 30% by weight, preferably at least 40% by weight, preferably at least 50% by weight, preferably at least 60% by weight, preferably at least 70% by weight, preferably at least 80% by weight, preferably at least 90% by weight, based on the total dry weight of the gelling agents. Even more preferably, alginates are the only gelling agents in the gelling beads.

Generally, these gelling agents are in the form of a salt, such as a sodium salt, magnesium salt, or potassium salt, preferably a sodium salt. Sodium alginate is particularly preferred.

Preferably, the gelling agent used has a Brookfield viscosity, measured at 20°C and 1%, of 2000 cps or less, preferably 1000 cps or less, preferably 800 cps or less, preferably 500 cps or less, preferably 400 cps or less, preferably 300 cps or less, preferably 250 cps or less, and preferably 200 cps or less. Preferably, the Brookfield viscosity is 10 cps or more, preferably 20 cps or more, preferably 30 cps or more, preferably 35 cps or more, preferably 50 cps or more, preferably 80 cps or more, and preferably 100 cps or more. The viscosity is selected within a range ranging, for example, from 35 to 65 cps, or from 100 to 200 cps, or from 300 to 400 cps.

Preferably, the content of gelling agent by dry weight (dry/dry), in particular the alginate content, relative to the total dry weight of the gelling beads is at least 0.1 wt.%, preferably at least 0.3 wt.%, preferably at least 0.5 wt.%, preferably at least 0.7 wt.%, preferably at least 1.0 wt.%, preferably at least 1.2 wt.%, preferably at least 1.4 wt.%. This dry/dry weight content of gelling agent, or more specifically alginate, is preferably 5.0 wt.% or less, preferably 4.0 wt.% or less, preferably 3.0 wt.% or less, preferably 2.0 wt.% or less, preferably 1.8 wt.% or less, preferably 1.6 wt.% or less.

Preferably, the gelling beads of the present invention have a dry weight ratio of isosorbide/gelling agent of 40 or more, preferably 50 or more, preferably 55 or more, preferably 60 or more. This ratio is preferably 200 or less, preferably 150 or less, preferably 140 or less, preferably 130 or less, preferably less than 120, preferably 100 or less, preferably 80 or less, preferably 75 or less.

Preferably, when alginate is used, the gelling beads of the present invention have a dry weight ratio of isosorbide/alginate of 40 or more, preferably 50 or more, preferably 55 or more, preferably 60 or more. This ratio is preferably 200 or less, preferably 150 or less, preferably 140 or less, preferably 130 or less, preferably less than 120, preferably 100 or less, preferably 80 or less, preferably 75 or less.

The gelling beads of the present invention comprise a solvent, preferably water, even more preferably demineralized water. Preferably, the solvent content of the gelling beads is 30% by weight or less, preferably 25% by weight or less, preferably 20% by weight or less, for example 18% by weight or less, based on the total weight of the gelling beads. This solvent content is generally 1% or more, or even 5% or more, or even 10% or more, for example 13%, 14%, or 15% or more.

Gelling beads may contain ions, generally in trace amounts, depending on the process used to prepare the beads.

Furthermore, the gelling beads may contain substances other than those listed above, provided that they do not disrupt the desired properties, particularly with regard to the taste quality and/or stability of the gelling beads and/or the pharmacological activity of isosorbide. Such other substances include, for example, flavoring agents, sweeteners, particularly high-intensity sweeteners, encapsulating agents such as cyclodextrins, and compounds that target the bioavailability of the active ingredients of the beads, such as active ingredients other than isosorbide, particularly those intended to modify the bioavailability of isosorbide.

Preferably, the gelling beads contain less than 30% by weight, preferably less than 20% by weight, preferably less than 10% by weight, preferably less than 5% by weight, preferably less than 1% by weight, preferably 0% by weight of other substances, based on the total weight of the gelling beads. Indeed, the examples below demonstrate that other substances are not essential to solve the problems posed herein.

Most preferably, the gelling beads contain no other substances. In particular, this means that the gelling beads consist solely of isosorbide, a gelling agent, and a solvent, preferably water, more preferably demineralized water. In an advantageous embodiment, the gelling beads consist solely of isosorbide, alginate, and a solvent, preferably water, more preferably demineralized water.

Preferably, the gelling beads have an average diameter of 5.0 mm or less, preferably 3.0 mm or less, preferably 2.0 mm or less, preferably 1.5 mm or less. This average diameter is generally 0.1 mm or more, or even 0.2 mm or more, or even 0.3 mm or more, or even 0.4 mm or more, or even 0.5 mm or more.

Preferably, the beads are insoluble in water at a temperature of 20°C.

The present invention also relates to a pharmaceutical composition comprising the gelling beads of the present invention. Isosorbide acts as an active ingredient in this pharmaceutical composition.

"Pharmaceutical composition" is intended to mean a composition in its final dosage form intended for administration to a patient.

The pharmaceutical composition may also consist solely of the gelling beads of the present invention. Therefore, the gelling beads may be administered as is. Alternatively, the gelling beads may be administered together with other substances, for example, in the form of a suspension of gelling beads in syrup.

Preferably, the pharmaceutical composition of the present invention contains isosorbide per dose in an amount of at least 10 g, preferably at least 20 g, preferably at least 25 g, e.g., 28 g.

Preferably, the pharmaceutical compositions of the present invention are intended to be administered once, twice, or three times daily, preferably three times daily.

Preferably, the pharmaceutical composition of the present invention contains an isosorbide content of at least 20% by dry weight, preferably at least 30% by weight, preferably at least 40% by weight, preferably at least 50% by weight, preferably at least 60% by weight, preferably at least 70% by weight, more preferably at least 75% by weight, more preferably at least 80% by weight, based on the total weight of the pharmaceutical composition. This isosorbide content by dry weight is generally not more than 95% by weight, or even not more than 90% by weight, or even not more than 85% by weight.

Preferably, the pharmaceutical composition according to the invention is for use as a medicament, in particular for treating Meniere's disease. Another subject of the invention is a method of treatment, in particular for Meniere's disease, comprising the administration of a pharmaceutical composition according to the invention. In other words, this is a composition for its use in the treatment of Meniere's disease. Furthermore, the invention also covers the use of a composition according to the invention for the manufacture of a medicament intended for therapeutic use in the treatment of Meniere's disease. Preferably, the patient to be treated is an individual suffering from Meniere's disease.

Another subject of the invention is also a process for preparing gelling beads according to the invention, comprising:
Step (a): preparing a solution comprising isosorbide and one or more gelling agents;
Step (b): preparing a gelling solution;
step (c) adding the solution prepared in step (a) dropwise to the gelling solution prepared in step (b);
Step (d) recovering the gelled beads of isosorbide thus obtained;
The present invention relates to a process including:

Preferably, for the preparation of the solution of step (a), the gelling agent is first dissolved in a solvent, preferably water, more preferably demineralized water, and then isosorbide is added.

Preferably, the solution of step (a) has an isosorbide content selected within a range spanning 30 to 80% by weight, relative to the total weight of the solution. Preferably, this content is 40% or more, preferably 45% or more, preferably 50% or more, preferably 55% or more. Preferably, this content is 80% or less, preferably 75% or less, preferably 70% or less, preferably 65% or less. This content is, for example, equal to 50% or 60%.

Preferably, the solution of step (a) has a gelling agent content, in particular an alginate content, selected within a range spanning 0.1 to 5.0% by weight, relative to the total weight of the solution. Preferably, this content is 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more. Preferably, this content is 4.5% or less, preferably 4.0% or less, preferably 3.5% or less, preferably 3.0% or less, preferably 2.5% or less, preferably 2.0% or less, preferably 1.5% or less, preferably 1.0% or less.

Preferably, the amounts of isosorbide and gelling agent in the solution of step (a) are selected so that the weight ratio of isosorbide/gelling agent is greater than or equal to 40, preferably greater than or equal to 50, preferably greater than or equal to 60. This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 110, preferably less than or equal to 100.

Preferably, when alginate is used, the amounts of isosorbide and alginate in the solution of step (a) are selected so that the weight ratio of isosorbide/alginate is 40 or more, preferably 50 or more, preferably 60 or more. This ratio is preferably 200 or less, preferably 150 or less, preferably 140 or less, preferably 110 or less, preferably 100 or less.

Preferably, the total amount of solids in the solution in step (a) is selected within a range of 30 to 80% by weight, based on the total weight of the solution. Preferably, this solids amount is selected within a range of 50 to 70%, preferably 60 to 65%.

Preferably, the gelling solution of step (b) contains one or more polyvalent metal ions. Indeed, it is envisioned that the gelling agent of the present invention is preferably a polymer capable of gelling by crosslinking in the presence of polyvalent metal ions. Alternatively, and depending on the gelling agent selected, the gelling solution may be a solution having a temperature lower than that of the solution of step (a), such that gelation occurs upon cooling.

These polyvalent metal ions are selected from, for example, calcium ions, aluminum ions, iron ions, copper ions, or zinc ions, or mixtures thereof. Calcium ions are particularly preferred. These calcium ions may preferably be in the form of inorganic salts such as calcium chloride, calcium sulfate, calcium hydrogen phosphate, or calcium carbonate. They may also be in the form of organic salts such as calcium lactate, calcium gluconate, or calcium citrate. These salts are preferably water-soluble. Most preferably, the polyvalent metal ions used in the present invention include at least calcium chloride. Even more preferably, calcium chloride is the only polyvalent metal ion used.

When the polyvalent metal ion is in the form of a water-insoluble salt (as is the case, for example, with calcium carbonate), it is necessary to add an acid to dissolve the salt, particularly salts of citric acid, adipic acid, glucono-delta-lactonic acid, etc. This is why it is preferable to use water-soluble calcium salts, especially calcium chloride.

Preferably, the gelling solution of step (b) has a polyvalent metal ion content, in particular a calcium chloride content, selected within a range spanning 1 to 20% by dry weight relative to the total weight of the solution. Preferably, this content is 3% or more, preferably 5% or more, preferably 7% or more, preferably 9% or more. Preferably, this content is 18% or less, preferably 16% or less, preferably 14% or less, preferably 12% or less, preferably 11% or less. This content is, for example, equal to 10%.

To carry out step (c), the solution of step (a) can be pumped from one storage unit to a gelling solution in another storage unit. The pump used typically depends on the viscosity of the gelling agent-containing solution of step (a). The solution prepared in step (a) can be added dropwise to the gelling solution prepared in step (b), allowing for the instantaneous formation of beads.

Preferably, the process for preparing gelling beads further comprises, between steps (c) and (d), a step of washing the gelling beads, preferably in demineralized water. This step is typically performed to remove salts used in the process, such as calcium chloride, from the product.

The process for preparing gelling beads preferably includes a step of drying the gelling beads between steps (c) and (d). This step is preferably after the washing step, if such a step is performed. This drying can be carried out in an oven. However, on an industrial scale, techniques using the action of a heated air stream applied to moving beads are preferred. One example is drying in an air-fluidized bed.

In addition to increasing the stability of the gelled beads, drying also has the effect of reducing the diameter of the beads. Therefore, to control the desired diameter, the effect of this heating step must be considered in addition to selecting a suitable system for forming droplets for gelation.

Preferably, before drying, the gelling beads contain a liquid core. Indeed, in this case, the drying step advantageously makes it possible to concentrate the isosorbide in the beads.

Preferably, after drying, the gelling beads contain no liquid core.

The present invention also relates to gelling beads, particularly gelling beads for oral administration, obtainable by or obtained by the process for preparing gelling beads of the present invention. Preferred embodiments of these gelling beads are as described above in the description of the gelling beads.

Another subject of the present invention relates to a method for masking the unpleasant taste of isosorbide, which method comprises placing said isosorbide in the form of gelling beads.

"Unpleasant taste" is intended to mean the taste and/or aroma as conventionally perceived by a set of individuals. In the context of isosorbide, this is typically its bitter taste.

Preferably, the gelling beads enable a statistically significant reduction in the bitter taste of isosorbide compared to an isosorbide solution having the same concentration and amount of isosorbide, and the bitter taste is detected by an electronic tongue (taste sensor) equipped with a bitter taste sensor having a lipid membrane, for example, using an instrument of the type Inset (registered trademark) Electronic Taste Sensing System TS-5000Z (Atsugichi-Chi, Japan) equipped with bitter taste sensors SB2AC0 (bitter 1, cationic substance), SB2AN0 (bitter 2, cationic substance), and SB2C00 (bitter 3, anionic substance).

Preferably, the gelling beads provide a statistically significant improvement in the taste of isosorbide compared to an isosorbide solution having the same concentration and amount of isosorbide, the improvement being assessed using a panel of tasters.

Alternatively, instead of comparing with an isosorbide solution of the same concentration, it is possible to compare with 40 mL of isosorbide solution containing 28 g of isosorbide, which represents the reference dose for treating Meniere's disease.

Preferably, the gelling beads make it possible to completely mask the unpleasant taste of isosorbide, in particular its bitter taste.

Preferably, the gelling beads are as described above.

Preferably, the isosorbide is incorporated into gelling beads formed by the process for preparing gelling beads of the present invention described above.

In this specification, amounts by "dry weight" are understood to refer to amounts by weight of anhydrous material. Conversely, unless otherwise indicated, amounts simply expressed by "weight" (typically part of a description of a preparation process) refer to the amount of material referred to as "commercial," i.e., the amount of a generally powdered product used as is. These weight contents therefore optionally include water inherently present in these commercial powders. In this regard, it should be noted that isosorbide and its salts typically contain preferably 0% water by weight, while gelling agents, particularly alginates, contain up to 15% water by weight.

The drawings and the following description substantially include specific elements that are specific in nature. Therefore, they may not only help to better understand the invention, but also contribute to identifying the invention as appropriate.

Ingredients: Demineralized water, isosorbide (Isosorbide C PHARMA, ROQUETTE, batch E2366), xylitol (XYLISORB® P90, ROQUETTE, batch E302Y), maltitol (SWEETPEARL® P90, ROQUETTE, batch EMM29), amylose-enriched pea maltodextrin (KLEPTOSE® Linecaps, ROQUETTE, batch E4118), hydroxypropyl-beta-cyclodextrin (KLEPTOSE® HPB, ROQUETTE, batch E0262), yellow pectin (LOUIS FRANCOIS, Batch 342CS), a compound of microcrystalline cellulose (MCC) and carboxymethyl cellulose (CMC) ("co-processed compound") (TABULOSE 591F, ROQUETTE, Batch 165004073), soluble hydrolyzed hydroxypropyl pea starch (LYCOAT® RS720, ROQUETTE, Batch E001R), aspartame (Ajinomoto), sodium saccharin (Sigma), sucralose (NIUTANG), citric acid (Sigma), low viscosity sodium alginate (1.0%, 35-5 at 20°C). 6 cps Brookfield viscosity) (Sodium alginate IL6G, AGI), medium viscosity sodium alginate (1.0%, 100-200 cps Brookfield viscosity at 20°C) (Sodium alginate I1G80, AGI), high viscosity sodium alginate (1.0%, 300-400 cps Brookfield viscosity at 20°C) (Sodium alginate I3G80, AGI), calcium chloride (Sigma), flavoring (MANE): Banana/Bitter Masking/Blackcurrant/Cherry/Herbal/Lemon/Mint/Orange Peach/Strawberry/Tutti Frutti/Chocolate/Caramel.

Example 1: Taste masking of isosorbide using intense sweeteners (liquid medium) Various liquid formulations were tested to evaluate the effectiveness of intense sweeteners in masking the taste of isosorbide. The formulations used are presented in Tables 1 and 2 below, with percentages expressed by weight relative to the total weight of the formulation.

The solution prepared in this manner was orally administered to a panel of five tasters.

The use of aspartame and sodium saccharin failed to reduce the bitter taste sensation caused by isosorbide. Substituting aspartame and sodium saccharin for sucralose failed to reduce the bitter taste sensation caused by isosorbide, nor did increasing the concentration of sucralose. The addition of maltitol and xylitol to the formulation also failed to improve the taste of the preparation.

Example 2: Taste masking of isosorbide using encapsulation technology (liquid medium) To evaluate the effectiveness of the complexation encapsulation technology in masking the taste of isosorbide, various liquid formulations were tested. The formulations used are presented in Tables 3 and 4 below, with percentages expressed by weight relative to the total weight of the formulation.

The solution prepared in this manner was orally administered to a panel of five tasters.

Regardless of the concentrations of hydroxypropyl-beta-cyclodextrin and pea maltodextrin used, the impact on bitterness was limited. For all formulations 9 to 14, a burnt caramel taste was perceived by the panel, but the bitterness could not be eliminated.

Example 3: Masking the taste of isosorbide using texture processing technology (gelling medium) To evaluate the effectiveness of texture processing technology in masking the taste of isosorbide, various formulations in gel form were tested. The formulations used are presented in Tables 5 and 6 below, with percentages expressed by weight relative to the total weight of the formulation. In preparing these formulations, the isosorbide was milled in advance (IKA mill) to facilitate its dissolution.

The gel prepared in this manner was orally administered to a panel of five tasters.

The use of MCC/CMC compounds and soluble hydrolyzed hydroxypropyl pea starch resulted in a somewhat viscous gel, depending on the concentration used. The use of yellow pectin resulted in a better texture.

Formulations containing MCC/CMC compounds as well as pectin had limited effect on the bitter taste of isosorbide, even when strong sweeteners were added to the formulations. Formulations based on soluble hydrolyzed hydroxypropyl pea starch were unable to improve the taste of isosorbide.

Example 4: Taste Masking of Isosorbide Using Flavorings with Texture Processing Technology (Gelling Medium) In this example, the inventors attempted to improve the gel of Example 3, which had only a limited effect on the bitter taste of isosorbide. To this end, gels with added flavorings were tested. The formulations used are presented in Tables 7 and 8 below, with percentages expressed by weight relative to the total weight of the formulation. In preparing these formulations, the isosorbide was pre-milled (in an IKA mill) to facilitate its dissolution. All flavorings listed in the "Ingredients" section above, namely the following flavorings, were tested: Banana/Bitter Masking/Blackcurrant/Cherry/Herbal/Lemon/Mint/Orange-Peach/Strawberry/Tutti Frutti/Chocolate/Caramel.

The flavored gel was orally administered to a panel of five tasters.

Again, the results were inconclusive, regardless of the flavor tested or its concentration. A strong bitter taste was still detected by the panel in all tests.

Example 5: Masking the taste of isosorbide by forming gelling beads To assess the effectiveness of this technology in masking the taste of isosorbide, various formulations in the form of gelling beads were tested.

First, the solutions [A] shown in Tables 9 and 10 below were prepared (percentages are expressed by weight relative to the total weight of the formulation).

Sodium alginate was dispersed in demineralized water and the whole was mixed using a high-shear mixer (POLYTRON type). Isosorbide was added after grinding to promote its dissolution.

Then, a gelling solution [B] consisting of 90% by weight demineralized water and 10% by weight calcium chloride was prepared.

For each solution [A], the following was done: Solution [A] was extracted using a pipette and then dropped into solution [B], instantly forming gelled beads. The beads thus formed were removed and rinsed with demineralized water in a beaker to remove residual calcium chloride.

The beads thus obtained had a diameter of approximately 2-3 mm. They were then dried in an oven, at which point they had a diameter of approximately 1 mm.

To determine whether the compounds in solution [A] had completely entered the gelled bead formation, a test was performed that consisted of introducing a blue dye into solution [A]. No staining of solution [B] was observed during bead formation, thus indicating that the compounds in solution [A] had substantially entered these beads.

Three different types of sodium alginate were tested for formulations 33-37: low viscosity alginate (35-65 cps), medium viscosity alginate (100-200 cps), and high viscosity alginate (300-400 cps). Satisfactory beads were obtained with all three alginates. However, the inventors noted that the medium viscosity alginate proved optimal, particularly with regard to drying efficiency of the gelling beads. This medium viscosity alginate was used in formulation 38.

The resulting gelled beads of isosorbide completely masked the bitter taste of isosorbide. When the isosorbide concentration in the solution (formulations 34 and 35) was increased, the beads became weaker compared to formulation 33. When the alginate concentration in the solution containing 50% isosorbide (formulations 36 and 37) was increased, beads without a liquid core (the beads were completely gelled) were obtained. It is recalled that the presence of a liquid core is advantageous at this stage, since it allows the isosorbide to be effectively concentrated by drying. Finally, the best beads were obtained from a solution [A] containing 60% isosorbide, 39% demineralized water, and 1.0% sodium alginate (formulation 38, isosorbide/alginate ratio = 60, solids content = 61%), and the next best beads were obtained from a solution [A] containing 50% isosorbide, 49.5% demineralized water, and 0.5% sodium alginate (formulation 33, isosorbide/alginate ratio = 100, solids content = 50.5%).

Beads obtained from formulation 38 were analyzed by gas chromatography with flame ionization detection and internal standard method to determine their content of isosorbide by dry weight.

The capillary column used was 30 meters long, had an inner diameter of 0.32 mm, and a film thickness of 1 μm.

The operating conditions were as follows: column temperature 140-250°C, ramped at 3°C/min, then ramped at 10°C/min to 300°C; injection temperature 300°C; detector temperature 300°C; vector gas helium, constant flow rate 1.7 mL/min; split injection mode, split flow rate 80 mL/min, hydrogen flow rate 30 mL/min, air flow rate 400 mL/min, injection volume 1 microliter.

100-150 mg of gelling beads and 30 mg of internal standard (methyl α-D-glucopyranoside) were placed in a 100 mL beaker. 10 mL of 10% sodium dodecyl sulfate and 50 mL of reverse osmosis purified water were added, and the whole was stirred to dissolve the gelling beads.

1 mL of the solution was added to 1 mL of pyridine and deposited in a 2 mL dish with a screw-top lid. The entire mixture was evaporated to dryness under a stream of nitrogen. The residue was re-taken in 1 mL of pyridine and 0.5 mL of BSTFA, and the deposit was separated by stirring or sonication. The entire mixture was dried in a bath, and the temperature was controlled at 70°C for 30 minutes before 1 microliter was injected.

The isosorbide content is expressed as dry weight (g) per 100g of gelling beads and is given by the following formula:

(In the formula,
Si = surface area of isosorbide,
Se = surface area of the internal standard peak,
Pe = weight of internal standard introduced into the beaker (mg),
P = weight of weighed beads (mg)
Ki = response factor for isosorbide (approximately 0.8 under the analytical conditions used herein).

Two samples were tested, which did not differ in the drying method used. The turbine-dried sample had an isosorbide content by dry weight of 81.7±0.9% (average made over 9 measurements) relative to the total weight of gelling beads. The oven-dried sample had an isosorbide content by dry weight of 83.6±1.0% (average made over 6 measurements) relative to the total weight of gelling beads.

Claims (10)

Gelling beads comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide based on the total weight of the gelling beads;
the gelling beads contain alginate as the only gelling agent;
the dry weight ratio of isosorbide/alginate is equal to or greater than 55 and less than 120;
Gelling beads having an average diameter of 5.0 mm or less . The gelling beads of claim 1, characterized in that the isosorbide content is at least 60% by dry weight of isosorbide, based on the total weight of the gelling beads. 3. The gelling beads according to claim 1 , wherein the content of the gelling agent is at least 0.1% by weight and not more than 5.0% by weight based on the total weight of the gelling beads, on a dry basis. 4. The gelling beads according to claim 1 , which have a water content of 30% by weight or less based on the total weight of the gelling beads. A pharmaceutical composition comprising or consisting of the gelling beads according to any one of claims 1 to 4 . 6. Pharmaceutical compositions according to claim 5 for their use as medicaments. A process for preparing the gelling beads according to any one of claims 1 to 6 , comprising:
Step (a): preparing a solution containing isosorbide and alginate ;
Step (b): preparing a gelling solution;
step (c) adding the solution prepared in step (a) dropwise to the gelling solution prepared in step (b);
Step (d) recovering the gelled beads of isosorbide thus obtained;
The process includes: 8. The process for preparing gelling beads of claim 7 , wherein the gelling solution of step (b) comprises one or more multivalent metal ions. 9. The process for preparing gelling beads according to claim 8 , wherein the polyvalent metal ions are selected from calcium ions, aluminum ions, iron ions, copper ions, or zinc ions, or mixtures thereof. 10. The process for preparing gelling beads according to claim 7 , further comprising a step of drying the gelling beads.